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Pgc-1beta, a novel pgc-1 homologue and uses thereforRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic AcidPgc-1beta, a novel pgc-1 homologue and uses therefor description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070009933, Pgc-1beta, a novel pgc-1 homologue and uses therefor. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a divisional application of U.S. Ser. No. 10/290,544 filed on Nov. 8, 2002, which claims priority to U.S. Provisional Application No. 60/338,126 filed on Nov. 9, 2001; each application is incorporated herein in its entirety by reference. BACKGROUND OF THE INVENTION [0003] The transcriptional function of many nuclear receptors (NRs) is regulated by ligand-dependent recruitment of coactivators to the carboxyl-terminal ligand-binding domain (Aranda, A., and Pascual, A. (2001) Physiol. Rev. 81:1269-1304; Rosenfeld, M. G. and Glass, C. K. (2001) J. Biol. Chem. 276:36865-36868). A number of coactivators, including the p160 family, p300/CBP and P/CAF, contain intrinsic histone acetyl transferase activity and regulate transcription by modulating histone acetylation (Aranda and Pascual (2001) supra). Other coactivators, consisting of heterogeneous proteins with little sequence homology, modulate transcription by acting as protein docking interfaces that recruit histone acetyl transferase-containing complexes or associate with basal transcription factors such as RNA polymerase II holoenzyme (Freedman, L. P. (1999) Cell 97:5-8). The interaction between NRs and many coactivators requires a conserved LXXLL motif (L is leucine and X is any amino acid), which is believed to form hydrophobic contacts with the receptors (Nolte, R. T. et al. (1998) Nature 395:137-143; Westin, S. et al. (1998) Nature 395:199-202). [0004] PGC-1 was initially identified as a PPAR.gamma.-interacting protein from a brown adipose tissue (BAT) library and was subsequently found to associate with an array of NRs and transcription factors (Puigserver, P. et al. (1998) Cell 92:829-839; Wu, Z. et al. (1999) Cell 98:115-124; Vega, R. B. et al. (2000) Mol. Cell. Biol. 20:1868-1876; Michael, L. F. et al. (2001) Proc. Natl. Acad. Sci. USA 98:3820-3825). Importantly, PGC-1 has been shown to coordinately regulate the program of mitochondrial biogenesis and adaptive thermogenesis in BAT and skeletal muscle, mainly through the coactivation of PPARs and nuclear respiratory factor 1 (NRF1), a nuclear transcription factor that regulates the expression of many mitochondrial genes (Puigserver et al. (1998) supra; Wu et al. (1999) supra). In transgenic mice, PGC-1 increases mitochondrial biogenesis and .beta.-oxidation of fatty acids in the heart, likely through augmentation of PPAR.alpha. and NRF1 transcriptional activity (Lehman, J. J. et al. (2000) J. Clin. Invest. 106:847-856). Recently, PGC-1 expression was found to be elevated in fasted liver and several models of type-1 and type-2 diabetes; in addition, PGC-1 can directly control the activation of hepatic gluconeogenesis (Yoon, J. C. et al. (2001) Nature 413:131-138; Herzig, S. et al. (2001) Nature 413:179-183). SUMMARY OF THE INVENTION [0005] The present invention is based, at least in part, on the discovery of novel members of the family of PGC-1 molecules, referred to herein as PGC-1.beta. nucleic acid and protein molecules (e.g., human and mouse PGC-1.beta.). The present invention is further based, at least in part, on the discovery that PGC-1.beta. is upregulated during brown fat determination/differentiation, but not during cold exposure. The present invention is further based, at least in part, on the discovery that PGC-1.beta. expression is upregulated in the liver during fasting. The present invention is further based, at least in part, on the discovery that PGC-1.beta. induces mitochondrial biogenesis and fatty acid oxidation gene expression in the liver and cultured murine myotubes. The present invention is further based, at least in part, on the discovery that PGC-1.beta. is highly expressed in brown adipose tissue (BAT)and the heart (tissues that contain high levels of mitochondria and substrate oxidation)and on the discovery that PGC-1.beta. is a potent coactivator of NRF1. The present invention is still further based, at least in part, on the discovery that host cell factor (HCF), a cellular protein that is involved in herpes simplex virus (HSV) infection and cell cycle regulation (Wilson, A. C. et al. (1993) Cell 74:115-125; Wilson, A. C. et al. (1997) Mol. Cell. Biol. 17:6139-6146), is a binding partner that upregulates the transcriptional activity of both the originally identified PGC-1, hereinafter referred to as PGC-1.alpha., and PGC-1.beta.. The present invention is further based, at least in part, on the discovery that both PGC-1.alpha. and PGC-1.beta. induce mitochondrial gene expression in neuroblastoma cells suggesting an important role in neurological disorders. The present invention is yet further based, at least in part, on the discovery that both PGC-1.alpha., and PGC-1.beta. induce the expression of enzymes involved in free radical metabolism such as superoxide dismutase (Mn-SOD) and glutathione peroxidase (GPx), suggesting an important role in the cellular defense against free radical damage. [0006] The PGC-1.beta. nucleic acid and protein molecules of the present invention are useful as modulating agents in regulating a variety of cellular processes, e.g., cellular determination and/or differentiation (e.g., brown adipose determination and/or differentiation), cellular metabolism, fatty acid oxidation, mitochondrial function and/or respiration, cellular signaling, and/or cellular proliferation. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding PGC-1.beta. proteins or biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of PGC-1.beta.-encoding nucleic acids. [0007] In one embodiment, a PGC-1.beta. nucleic acid molecule of the invention is at least 50%, 55%, 60%, 65%, 70%, 71%, 72%, 73%, 74%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.99% or more identical to the nucleotide sequence (e.g., to the entire length of the nucleotide sequence) shown in SEQ ID NO:1, 3, 4, or 6, or a complement thereof. [0008] In a preferred embodiment, the isolated nucleic acid molecule includes the nucleotide sequence shown in SEQ ID NO:1, 3, 4, or 6, or a complement thereof. In another preferred embodiment, the isolated nucleic acid molecule includes nucleotides 1-660 of SEQ ID NO:3. In another preferred embodiment, the isolated nucleic acid molecule comprises nucleotides 1-1140 of SEQ ID NO:3. In another preferred embodiment, the nucleic acid molecule consists of the nucleotide sequence shown in SEQ ID NO:1, 3, 4, or 6. [0009] In another embodiment, a PGC-1.beta. nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence sufficiently identical to the amino acid sequence of SEQ ID NO:2 or 5. In a preferred embodiment, a PGC-1.beta. nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 71%, 72%, 73%, 74%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.99% or more identical to the entire length of the amino acid sequence of SEQ ID NO:2 or 5. [0010] In another preferred embodiment, an isolated nucleic acid molecule encodes the amino acid sequence of human PGC-1.beta.. In another preferred embodiment, an isolated nucleic acid molecule encodes the amino acid sequence of mouse PGC-1.beta.. In yet another preferred embodiment, the nucleic acid molecule includes a nucleotide sequence encoding a protein having the amino acid sequence of SEQ ID NO:2 or 5. In yet another preferred embodiment, the nucleic acid molecule is at least 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 457, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, 3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550, 3600 or more nucleotides in length. In a further preferred embodiment, the nucleic acid molecule is at least 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 457, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, 3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550, 3600 or more nucleotides in length and encodes a protein having a PGC-1.beta. activity (as described herein). [0011] Another embodiment of the invention features nucleic acid molecules, preferably PGC-1.beta. nucleic acid molecules, which specifically detect PGC-1.beta. nucleic acid molecules relative to nucleic acid molecules encoding non-PGC-1.beta. proteins. For example, in one embodiment, such a nucleic acid molecule is at least 20, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 457, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, 3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550, 3600 or more nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO:1 or 4, or a complement thereof. [0012] In preferred embodiments, the nucleic acid molecules are at least 15 (e.g., 15 contiguous) nucleotides in length and hybridize under stringent conditions to the nucleotide molecules set forth in SEQ ID NO:1 or 4. [0013] In other preferred embodiments, the nucleic acid molecule encodes a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5, wherein the nucleic acid molecule hybridizes to a complement of a nucleic acid molecule comprising SEQ ID NO:1, 3, 4, or 6, respectively, under stringent conditions. [0014] Another embodiment of the invention provides an isolated nucleic acid molecule which is antisense to a PGC-1.beta. nucleic acid molecule, e.g., the coding strand of a PGC-1.beta. nucleic acid molecule. [0015] Another aspect of the invention provides a vector comprising a PGC-1.beta. nucleic acid molecule. In certain embodiments, the vector is a recombinant expression vector. In another embodiment, the invention provides a host cell containing a vector of the invention. In yet another embodiment, the invention provides a host cell containing a nucleic acid molecule of the invention. The invention also provides a method for producing a protein, preferably a PGC-1.beta. protein, by culturing in a suitable medium, a host cell, e.g., a mammalian host cell such as a non-human mammalian cell, of the invention containing a recombinant expression vector, such that the protein is produced. [0016] Another aspect of this invention features isolated or recombinant PGC-1.beta. proteins and polypeptides. In one embodiment, an isolated PGC-1.beta. protein includes at least one or more of the following domains: an LXXLL motif, an RRM, an AD, an HBM, and/or a glutamic/aspartic acid rich acidic domain. [0017] In a preferred embodiment, a PGC-1.beta. protein includes at least one or more of the following domains: an LXXLL motif, an RRM, an AD, an HBM, and/or a glutamic/aspartic acid rich acidic domain, and has an amino acid sequence at least about 50%, 55%, 60%, 65%, 67%, 68%, 70%, 71%, 72%, 73%, 74%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.99% or more identical to the amino acid sequence of SEQ ID NO:2 or 5. [0018] In another preferred embodiment, a PGC-1.beta. protein includes at least one or more of the following domains: an LXXLL motif, an RRM, an AD, an HBM, and/or a glutamic/aspartic acid rich acidic domain, and has a PGC-1.beta. activity (as described herein). [0019] In yet another preferred embodiment, a PGC-1.beta. protein includes at least one or more of the following domains: an LXXLL motif, an RRM, an AD, an HBM, and/or a glutamic/aspartic acid rich acidic domain, and is encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under stringent hybridization conditions to a complement of a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6. [0020] In another embodiment, the invention features fragments of the protein having the amino acid sequence of SEQ ID NO:2 or 5, wherein the fragment comprises at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 amino acids (e.g., contiguous amino acids) of the amino acid sequence of SEQ ID NO:2 or 5. In another embodiment, a PGC-1.beta. protein has the amino acid sequence of SEQ ID NO:2 or 5. [0021] In another embodiment, the invention features a PGC-1.beta. protein which is encoded by a nucleic acid molecule consisting of a nucleotide sequence at least about 50%, 55%, 60%, 65%, 70%, 71%, 72%, 73%, 74%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.99% or more identical to a nucleotide sequence of SEQ ID NO:1, 3, 4, or 6, or a complement thereof. This invention further features a PGC-1.beta. protein which is encoded by a nucleic acid molecule consisting of a nucleotide sequence which hybridizes under stringent hybridization conditions to a complement of a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6, or a complement thereof. [0022] The proteins of the present invention or portions thereof, e.g., biologically active portions thereof, can be operatively linked to a non-PGC-1.beta. polypeptide (e.g., heterologous amino acid sequences) to form fusion proteins. The invention further features antibodies, such as monoclonal or polyclonal antibodies, that specifically bind proteins of the invention, preferably PGC-1.beta. proteins. In addition, the PGC-1.beta. proteins or biologically active portions thereof can be incorporated into pharmaceutical compositions, which optionally include pharmaceutically acceptable carriers. Continue reading about Pgc-1beta, a novel pgc-1 homologue and uses therefor... Full patent description for Pgc-1beta, a novel pgc-1 homologue and uses therefor Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Pgc-1beta, a novel pgc-1 homologue and uses therefor patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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